Investigation of diabetic glomerular pathophysiology is the focus of this proposed research project. We have found after three months of diabetes that 1) glomerular filtration rate and plasma flow is reduced, 2) arteriolar resistances are increased and 3) albumin excretion is elevated. Our first objective is to further evaluate glomerular hemodynamics and permselectivity during the first twelve months of experimental diabetes in the rat. This will be performed in untreated and insulin treated diabetic animals. The second aim of this project is to delineate the causal mechanisms of the increased arteriolar resistance. This will be approached by utilizing pharmacological blockade of known vasoactive systems (renin-angiotensin and adrenergic systems). Since sorbitol has been shown to accumulate in human diabetic glomeruli, the effects of inhibition of sorbitol production using an aldose reductase inhibitor will be evaluated to establish the importance of this substance in glomerular pathophysiology. Micropuncture techniques will be used to determine single nephron glomerular hemodynamics. Whole kidney hemodynamics will also be measured. The permselectivity of the glomerular filtration barrier will be evaluated using polydispersed radiolabelled dextran or dextran sulfate clearances. Thus, permeability as a function of molecular size and charge will be determined. These functional measurements will be correlated with the acid-base status, fluid volume status and glomerular morphological assessment in each experimental study. The results will be analyzed to obtain 1) an integrated description of diabetic glomerular hemodynamics and filtration barrier permselectivity as they relate to structural changes and 2) a further understanding of the causal mechanisms of elevated arteriolar resistance.